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Abstract: Acetaminophen overdose is one of the leading causes of acute liver failure and liver transplantation in the Western world. Magnesium is essential in several cellular processess. The Cyclin M family is involved in magnesium transport across cell membranes. Herein, we identify that among all magnesium transporters, only Cyclin M4 expression is upregulated in the liver of patients with acetaminophen overdose, with disturbances in magnesium serum levels. In the liver, acetaminophen interferes with the mitochondrial magnesium reservoir via Cyclin M4, affecting ATP production and reactive oxygen species generation, further boosting endoplasmic reticulum stress. Importantly, Cyclin M4 mutant T495I, which impairs magnesium flux, shows no effect. Finally, an accumulation of Cyclin M4 in endoplasmic reticulum is shown under hepatoxicity. Based on our studies in mice, silencing hepatic Cyclin M4 within the window of 6 to 24 h following acetaminophen overdose ingestion may represent a therapeutic target for acetaminophen overdose induced liver injury.
Fuente: Nature Communications, 2022, 13(1), 6816
Publisher: Nature Publishing Group
Year of publication: 2022
No. of pages: 21
Publication type: Article
DOI: 10.1038/s41467-022-34262-0
ISSN: 2041-1723
Spanish project: PID2020-117116RB-I00
Publication Url: https://doi.org/10.1038/s41467-022-34262-0
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GONZÁLEZ-RECIO, IRENE
SIMÓN, JORGE
GOIKOETXEA-USANDIZAGA, NAROA
SERRANO-MACIÁ, MARINA
MERCADO-GÓMEZ, MARIA
RODRÍGUEZ-AGUDO, RUBÉN
LACHIONDO-ORTEGA, SOFÍA
GIL-PITARCH, CLÀUDIA
FERNÁNDEZ-RODRÍGUEZ, CARMEN
CASTELLANA, DONATELLO
LATASA, MARIA U
ABECIA, LETICIA
ANGUITA, JUAN
DELGADO, TERESA C
IRUZUBIETA, PAULA
JAVIER CRESPO GARCIA
HARDY, SERGE
PETROV, PETAR D
JOVER, RAMIRO
AVILA, MATÍAS A
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